Vascular treatment method and apparatus

ABSTRACT

This invention relates to the method of use of a congener of an endothelium-derived bioactive composition of matter, which comprises administering said congener percutaneously to a site proximately adjacent the exterior of a coronary blood vessel at a therapeutically effective dosage.

This application is a 371 of PCT/US95/09055 filed on Jun. 23, 1995.

BACKGROUND OF THE INVENTION

This invention relates to methods and devices for the site-specificdelivery of bioactive agents in mammals, especially for cardiac andperipheral vascular applications, and more particularly, is directed toa method for treating the heart by intrapericardial access.

1. Pathophysiological Background

A. Vascular Endothelium Function

Normal blood vessels are lined with a layer of endothelial cells. Theendothelium releases local factors (endothelium-derived relaxing factornitric oxide! and prostaglandin I₂ PGI₂, or prostacyclin!) into thevessel wall (intramural release) and into the blood stream (intraluminalrelease). These factors maintain vascular tone (vessel relaxation),inhibit clot formation on the vessel inner surface (platelet adhesionand aggregation), inhibit monocyte adherence and chemotaxis, and inhibitsmooth muscle cell migration and proliferation. Normal endotheliumreleases both prostacyclin and nitric oxide in response to plateletaggregation. Nitric oxide release inhibits platelet adhesion, preventsfurther aggregation, and promotes platelet disaggregation. Prostacyclinrelease, promoted by platelet-derived thromboxane A₂, actssynergistically with nitric oxide to prevent platelet-mediatedvasoconstriction. As a result of this process, vasodilation andthrombolysis occurs, and blood flow is maintained. If the endothelium isdysfunctional or damaged, however, nitric oxide and prostacyclin releaseis impaired. Platelet aggregation and adhesion can occur unopposed, withplatelet-derived products acting directly on the smooth muscle cells tocause vasoconstriction. The net result is a blood vessel which is highlysusceptible to thrombosis and vasospasm. See, "Nitric oxide releaseaccounts for the biological activity of endothelium-derived relaxingfactor", Palmer R., et al., NATURE, 327:524, 1987; "Control of coronaryvascular tone by nitric oxide", Kelm M., et al., CIRC. RES., 66:1561,1990; "Regulatory functions of the vascular endothelium", Vane J., etal., N. ENGL. J. MED., 323:27, 1990; "Endothelial modulation of vasculartone: Relevance to coronary angioplasty and restenosis", Harrison D., J.AMER. COL. CARDIOL., 17:71B, 1991; "The antiaggregating properties ofvascular endothelium: Interactions between prostacyclin and nitricoxide", Radomski M., et al., BRIT. J. PHARMACOL., 92: 639, 1987; "EDRFincreases cyclic GMP in platelets during passage through the coronaryvascular bed", Pohl U., et al., CIRC. RES., 65:1798, 1989; "Humanendothelial cells inhibit platelet aggregation by separately stimulatingplatelet cAMP and cGMP", Alheid U., et al., EUROP. J. PHARMACOL.,164:103, 1989; "Nitric oxide: An endogenous modulator of leukocyteadhesion", Kubes P., et al., PROC. NATL. ACAD. SCI., 88:4651, 1991;"Nitric oxide and prostacyclin: Divergence of inhibitory effects onmonocyte chemotaxis and adhesion to endothelium in vitro", Bath P., etal., ARTERIOSCLER. THROMB., 11:254, 1991; "Nitric oxide generatingvasodilators and 8-Br-cGMP inhibit mitogenesis and proliferation ofcultured rat vascular smooth muscle cells", Garg U., et al., J. CLIN.INVEST., 83:1774, 1989; "Role of blood platelets and prostaglandins incoronary artery disease", Mehta J., et al., AMER. J. CARDIOL., 48:366,1981; and "Prostaglandins and cardiovascular disease: A review",Jacobsen D., SURGERY, 93:564, 1983.

B. Vascular Stenosis

Atherosclerosis can form within a blood vessel over a period of yearsfrom a variety of causes. The resulting lesion, or plaque, mayprogressively occlude the vessel and impede blood flow to vital organs.The stenotic lesions when covered by endothelium are termed stable. See,"Cellular proliferation in atherosclerosis and hypertension", SchwartzS., et al., PROG. CARDIOVASC. DIS., 26:355, 1984; and "The pathogenesisof atherosclerosis: An update", Ross R., N. ENGL. J. MED., 314:488,1986.

Unstable stenotic lesions are associated with endothelial cell injury atthe sites of coronary stenosis. Injury to the endothelium stops thelocal release of the endothelium-derived factors. Severe injury to thevessel wall exposes the underlying collagen layer, which immediatelyactivates platelet adhesion and aggregation (clumping) and stimulatesvasoconstriction (spasm). The platelet blood clotting cascade istriggered, thrombin and fibrin quickly form at the site(s) of vascularinjury, and a thrombus begins forming. The aggregating platelets releaselocal growth factor (platelet-derived growth factor or PDGF) whichactivates smooth muscle cells within the vessel wall. Over a period ofdays-to-weeks, smooth muscle cells migrate into the thrombus andproliferate, and the thrombus becomes organized. See, "The restenosisparadigm revisited: An alternative proposal for cellular mechanisms",Schwartz R., et al., J. AMER. COL. CARDIOL., 20:1284, 1992; "Thepathogenesis of coronary artery disease and the acute coronarysyndromes: Parts I and II", Fuster V., et al., N. ENGL. J. MED., 326:242and 310, 1992; "Migration of smooth muscle and endothelial cells",Casscells W., CIRC., 86:723, 1992; "The role of platelets, thrombin andhyperplasia in restenosis after coronary angioplasty", Ip J., et al., J.AMER. COL. CARDIOL., 17:77B, 1991; "Syndromes of acceleratedatherosclerosis: Role of vascular injury and smooth muscle cellproliferation", Ip J., et al., J. AMER. COL. CARDIOL., 15:1667, 1990;"Time course of smooth muscle cell proliferation in the intima and mediaof arteries following experimental angioplasty", Hanke H., et al., CIRC.RES., 67:651, 1990; "Effect of platelet factors on migration of culturedbovine aortic endothelial and smooth muscle cells", Bell L., et al.,CIRC. RES., 65:1057, 1989; "Role of platelets in smooth muscle cellproliferation and migration after vascular injury in rat carotidartery", Fingerle J., et al., PROC. NATL. ACAD. SCI., 86:8412, 1989;"Restenosis after coronary angioplasty: Potential biologic determinantsand role of intimal hyperplasia", Liu M., et al., CIRC., 79:1374, 1989;"Is vasospasm related to platelet deposition?", Lam J., et al., CIRC.,75:243, 1988; "Role of platelets and thrombosis in mechanisms of acuteocclusion and restenosis after angioplasty", Harker L., AMER. J.CARDIOL., 60: 20B, 1987; and "Restenosis after arterial angioplasty: Ahemorrheologic response to injury", Chesebro J., et al., AMER. J.CARDIOL., 60:10B, 1987.

C. Coronary Artery Stenosis

The described vasoconstrictive physiologic mechanisms occur both inperipheral and in coronary arteries, but the consequences of theprocesses are more life threatening in the coronary arteries. Coronaryarteries, the arteries of the heart, perfuse the cardiac muscle withoxygenated arterial blood. They provide essential nutrients and allowfor metabolic waste and gas exchange. These arteries are subject tounremitting service demands for continuous blood flow throughout thelife of the patient. A severe proximal coronary artery stenosis withendothelial injury induces cyclic coronary flow reductions ("CFR's").These are periodic or spasmodic progressive reductions in blood flow inthe injured artery. Episodes of CFR's are correlated to clinical acuteischemic heart disease syndromes, which comprise unstable angina, acutemyocardial infarction and sudden death. The common pathophysiologic linkis endothelial injury with vasospasm and/or thrombus formation.

Coronary artery disease is the leading cause of death in the UnitedStates today. In 1992, the clinical population of unstable anginapatients in the United States numbered approximately 1,000,000. Of thesepatients, it is estimated that 160,000 underwent coronary thrombolysistherapy where a clot dissolving agent is injected intravenously orintracoronary to reopen the thrombosed vessel and reduce the incidenceof myocardial infarction and sudden death. See, "Mechanisms contributingto precipitation of unstable angina and acute myocardial infarction:Implications regarding therapy", Epstein S., et al., AMER. J. CARDIOL.,54:1245, 1984; "Unstable angina with fatal outcome: Dynamic coronarythrombosis leading to infarction and/or sudden death", Falk E., CIRC.,71:699, 1985; "Speculation regarding mechanisms responsible for acuteischemic heart disease syndromes", Willerson J., et al., J. AMER. COL.CARDIOL., 8:245, 1986; "Platelets and thrombolytic therapy", Coller B.,N. ENGL. J. MED., 322:33, 1990; and "Frequency and severity of cyclicflow alterations and platelet aggregation predict the severity ofneointimal proliferation following experimental coronary stenosis andendothelial injury", Willerson J., et al., PROC. NATL. ACAD. SCI.,88:10624, 1991.

2. Surgical Procedures for Coronary Artery Disease

A. Procedures

Historically, the treatment of advanced atherosclerotic coronary arterydisease (i.e., beyond that amenable to therapy via medication alone) hasinvolved cardiac surgery in the form of a coronary artery bypass graft("CABG"). The patient is placed on cardiopulmonary bypass (heart-lungmachine) and the heart muscle is temporarily stopped (cardioplegia).Repairs are then surgically affected on the heart in the form of detourconduit grafted vessels (vein or artery graft) providing blood flowaround the coronary artery obstruction(s). While CABG surgery has beenshown to be effective, it carries with it inherent surgical risk andrequires a recuperation period of several weeks. During 1992,approximately 290,000 patients underwent CABG surgery in the UnitedStates.

A major advance in the treatment of atherosclerotic coronary arterydisease occurred in the late 1970's with introduction of theless-invasive percutaneous transluminal coronary angioplasty ("PTCA")procedures. The PTCA technique involves the retrograde introduction,from an artery in the leg or arm, up to the area of coronary vascularstenosis, of a catheter with a small dilating balloon at its tip. Thecatheter is advanced through the arteries via direct fluoroscopicguidance and passed across the luminal narrowing of the vessel. Once inplace the catheter balloon is inflated for a short period of time. Thisresults in mechanical deformation of the lesion or vessel with asubsequent increase in the cross-sectional area. This in turn reducesobstruction and transluminal pressure gradients, and increases bloodflow through the coronary artery. PTCA or angioplasty is a term that nowmay include other percutaneous transluminal methods of decreasingstenosis within a blood vessel, and includes not only balloon dilation,but also thermal ablation and mechanical atherectomy with shaving,extraction or ultrasonic pulverization of the lesion. During 1992 in theUnited States, it is estimated that some 400,000 patients underwentcoronary angioplasty procedures.

B. The Problem of Vascular Restenosis

Despite the major therapeutic advances in the treatment of coronaryartery disease represented by thrombolytic therapy, CABG operations andPTCA procedures, the success of these measures has been hampered by thedevelopment of vessel renarrowing or reclosure, most significantly inpatients undergoing thrombolysis and angioplasty procedures. Abruptvessel occlusion or early restenosis may develop during a period ofhours to days post-procedure due to vasospasm and/or platelet thrombusformation at the site of vessel injury. The more common and majorlimitation, however, is a development of progressive reversion of thediseased vessel to its previous stenotic condition, negating any gainsachieved from the procedure. This gradual renarrowing process isreferred to as restenosis or intimal hyperplasia. Restenosis is areparative response to endovascular injury after angioplasty and in veingrafts following vessel bypass surgery. The sequence of events issimilar to that described above for unstable lesions associated withendothelial injury, progressing through the process of plateletaggregation, vasoconstriction, thrombus formation, PDGF release, smoothmuscle cell proliferation, and thrombus organization.

Clinical studies indicate that thrombolytic therapy is ineffective inabout 20% of the treated patients and that 20% of those patientsinitially responding to therapy develop vessel rethrombosis within oneweek. Clinical studies also indicate that significant restenosis occursin about 40% of the PTCA patients within six months and in about 20% ofthe CABG patients within one year. This complication results inincreased morbidity, need for repeating the procedure, and escalatingmedical costs. With an estimated 690,000 coronary revascularizationprocedures performed in the United States in 1992, these incidences meanas many as 200,000 patients may develop vessel restenosis within oneyear after operation. Repeat procedures could account for $2.85 billionin additional health care costs in the United States.

6. Lack of Success in Prevention of Vasular Restenosis WithoutSide-Effects

At present, no therapy is know that consistently prevents the majorclinical problem of vascular restenosis. Intravenous medications havebeen tried as a means to prevent PTCA restenosis and other coronarydisease syndromes. Systemically administered pravastatin (U.S. Pat. No.4,346,227) and lovastatin (U.S. Pat. No. 5,140,012), both HMG CoAreductase inhibitors, have been said to prevent restenosis followingangioplasty. Prostaglandin E₁ ("PGE₁ ", a congener ofendothelium-derived PGI₂ and prostacyclin) and a known potentvasodilator with antiplatelet, anti-inflammatory and antiproliferativeeffects--see "Hemodynamic effects of prostaglandin E₁ infusion inpatients with acute myocardial infarction and left ventricular failure",Popat K., et al., AMER. HEART J., 103:485, 1982; "Comparison ofequimolar concentrations of iloprost, prostacyclin, and prostaglandin E₁on human platelet function", Fisher C., et al., J. LAB. CLIN. MED., 109:184, 1987; and "Prostaglandin E₁ inhibits DNA synthesis in arterialsmooth muscle cells stimulated with platelet-derived growth factors",Nilsson J., et al., ATHEROSCLEROSIS, 53:77, 1984--has been reported toinhibit abrupt occlusion and early restenosis in patients when infusedintravenously after PTCA for 12 hours at dosages of from 20 to 40ng/kg/min following a 65 ng bolus given intracoronary before and afterPTCA, "Prostaglandin E₁ infusion after angioplasty in humans inhibitsabrupt occlusion and early restenosis", See J., et al., ADV.PROSTAGLANDIN, THROMBOXANE AND LEUKOTRIENE RES., 17:266, 1987. However,prostacyclin (PGI₂) did not lower the coronary restenosis rate at 5months following PTCA, although infused intravenously for 48 hours afterPTCA at dosages of 5.0 ng/kg/min following intracoronary infusion at 7.0ng/kg/min before and after the PTCA procedure, "Effect of short-termprostacyclin administration on restenosis after percutaneoustransluminal coronary angioplasty", Knudtson M., et al., J. AMER. COL.CARDIOL., 15:691, 1990.

Sodium nitroprusside and other organic nitrates including nitroglycerinhave long been used as vasodilator agents, and investigations, citedabove, have shown that nitric oxide is the endogenousendothelium-derived nitrovasodilator. These agents also haveanti-platelet effects, "The interaction of sodium nitroprusside withhuman endothelial cells and platelet: Nitroprusside and prostacyclinsynergistically inhibit platelet function", Levin R., et al., CIRC.,66:1299, 1982; "Platelets, vasoconstriction, and nitroglycerin duringarterial wall injury: A new antithrombotic role for an old drug", LamJ., et al., CIRC., 78:7122, 1988. In a study in stenosed andendothelium-injured canine coronary arteries, promotion of endogenousnitric oxide production by infusion of L-arginine (the precursor fornitric oxide synthesis), at a dosage of 60 mg/kg, decreased plateletaggregation and abolished CFR's, "Endogenous nitric oxide protectsagainst platelet aggregation and cyclic flow variations in stenosed andendothelium-injured arteries", Yao S., et al., CIRC., 86: 1302, 1992.Intravenous nitroglycerin infusion at dosages from 10 to 15 μg/kg/mininhibited CFR's in stenosed and endothelium-injured coronary arteries ofdogs. This effect was potentiated by the pretreatment with the reducedthiol, N-acetylcysteine, at a dose of 100 mg/kg for 30 minutes,"Intravenous nitroglycerin infusion inhibits cyclic blood flow responsescaused by periodic platelet thrombus formation in stenosed caninecoronary arteries", Folts J., et al., CIRC., 83:2122, 1991. Sodiumnitroprusside is also a nitric oxide donor agent, "Metabolic activationof sodium nitroprusside to nitric oxide in vascular smooth muscle",Kowaluk E., et al., J. PHARMACOL. EXPER. THERAPEUTICS, 262:916, 1992.

The difficulty with systemic infusion of PGE₁, PGI₂, prostacyclin,sodium nitroprusside and the other organic nitrates is that, in dosageshigh enough to provide signs of beneficial cardiac effect, the potentvasodilator and antiplatelet effects of these bioactive agents alsoproduce systemic side effects of bleeding and hypotension. No knowtherapy consistently prevents acute coronary thrombosis and chronicvascular restenosis while reducing the systemic side-effects of bleedingand hypotension. See, "Prevention of restenosis after percutaneoustransluminal coronary angioplasty: The search for a `magic bullet`",Hermans W., et al., AMER. HEART J., 122:171, 1991; and "Clinical trialsof restenosis after coronary angioplasty", Popma J., et al., CIRC.,84:1426, 1991.

Recently, site-specific drug delivery to the arterial wall has become anew strategy for the treatment of vascular diseases, including vesselrestenosis following PTCA. These drug delivery systems include: (1)intravascular devices for site-specific (coronary artery) drug deliverycomprising double-balloon catheters, porous balloon catheters,microporous balloon catheters, channel balloon catheters, balloon overstent catheters, hydrogel coated balloon catheters, iontophoreticballoon catheters and stent devices; (2) periadventitial and epicardialdrug delivery devices, requiring surgical implantation, which includedrug-eluting polymer matrices and a iontophoretic patch device; and (3)intramural injection of drug-eluting microparticles. All of thesemethods are limited by certain problems including additional trauma tothe vessel wall, rapid washout of drug, need for invasive insertion,and/or use of therapeutic agents having a single mechanism of action.See, "Effect of controlled adventitial heparin delivery on smooth muscleproliferation following endothelial injury", Edelman E., et al., PROC.NATL. ACAD. SCI., 87:3773, 1990; "Localized release of perivascularheparin inhibits intimal proliferation after endothelial injury withoutsystemic anticoagulation", Okada T., et al., NEUROSURGERY, 25:892, 1989;"lontophoretic transmyocardial drug delivery: A novel approach toantiarrhythmic drug therapy", Avitall B., et al., CIRC., 85:1582, 1992;"Direct intraarterial wall injection of microparticles via a catheter: Apotential drug delivery strategy following angioplasty", Wilensky R., etal., AMER. HEART J., 122: 1136, 1991; "Local anticoagulation withoutsystemic effect using a polymer hepatin delivery system", Okada T., etal., STROKE, 19:1470, 1988.

Intrapericardial injection of drugs has been used for the treatment ofmalignant or loculated pericardial effusions in man. Drugs that havebeen injected into the pericardial space include antibiotic,antineoplastic, radioactive and fibrinolytic agents. This method ofsite-specific drug delivery has been shown to be effective in attaininghigher, longer-lasting drug levels in the pericardial fluid with lowerplasma concentrations and less systemic toxicity. It has been reportedthat no major complications were associated with the intrapericardialdrug infusion catheter and that it was possible to repeat the procedurewithout difficulty. See, "Intrapericardial instillation of platin inmalignant pericardial effusion", Fiorentino M., et al., CANCER, 62:1904,1988; and "Use of streptokinase to aid drainage of postoperativepericardial effusion", Cross J., et al., BRIT. HEART J., 62:217, 1989.

Intrapericardial drug delivery has not been clinically utilized forheart-specific treatments where pericardial pathology is normal,however, because the pericardial space is normally small and verydifficult to access without invasive surgery or risk of cardiac injuryby standard needle pericardiocentesis techniques. The pericardiocentesisprocedure is carried out by experienced personnel in the cardiaccatheterization laboratory, with equipment for fluoroscopy andmonitoring of the electrocardiogram. Complications associated withneedle pericardiocentesis include laceration of a coronary artery or theright ventricle, perforation of the right atrium or ventricle, punctureof the stomach or colon, pneumothorax, arrhythmia, tamponade,hypotension, ventricular fibrillation, and death. The complication ratesfor needle pericardiocentesis are increased in situations where thepericardial space and fluid effusion volume is small (i.e., thepericardial size is more like normal).

SUMMARY OF THE INVENTION

It is an object of this invention to treat the heart with drugs havingcardio-active or cardiovascular active effect by delivering those drugsfrom the pericardial space for "outside-in" effect. Such drugs includedrugs selected from vasodilator, antiplatelet, anticoagulant,thrombolytic, anti-inflammatory, antiarrhythmic, inotropic, antimitotic,angiogenic, antiatherogenic and gene therapy agents.

It is an object of this invention to provide treatment of vascularthrombosis and angioplasty restenosis, particularly coronary vascularthrombosis and angioplasty restenosis, thereby to decrease incidence ofvessel rethrombosis, unstable angina, myocardial infarction and suddendeath.

It is an object of this invention to prevent coronary angioplastyrestenosis, thereby to improve the results of the procedure, to decreaseneed for additional intervention and to lower health care costs.

An object of this invention is to provide nonsystemic, site-specific andtime extended administration of bioactive substances at low dosageseffective to achieve a desired treatment effect and localized so as notto generalize the effect systemically.

An object of this invention is to impart thrombolytic, vasodilator,antithrombotic and antiproliferative actions to injured coronary vesselswith reduced systemic effects.

An object of this invention is to provide delivery systems forsite-specific pharmacologic therapy effective to prevent venous bypassgraft thrombosis and intimal hyperplasia in coronary artery surgerypatients.

These and other objects and benefits of our invention will becomeapparent from the description of our invention that now follows.

We have discovered that administration of a congener of anendothelium-derived bioactive agent, more particularly anitrovasodilator, representatively the nitric oxide donor agent sodiumnitroprusside, to an extravascular treatment site, at a therapeuticallyeffective dosage rate, is effective for abolishing CFR's while reducingor avoiding systemic effects such as supression of platelet function andbleeding. By "extravascular treatment site", we mean a site proximatelyadjacent the exterior of the vessel. In accordance with our invention,congeners of an endothelium-derived bioactive agent includeprostacyclin, prostaglandin E₁, and a nitrovasodilator agent.Nitrovasodilater agents include nitric oxide and nitric oxide donoragents, including L-arginine, sodium nitroprusside and nitroglycycerine.The so administered nitrovasodilators are effective to provide one ormore of the therapeutic effects of promotion of vasodilation, inhibitionof vessel spasm, inhibition of platelet aggregation, inhibition ofvessel thrombosis, and inhibition of platelet growth factor release, atthe treatment site, without inducing systemic hypotension oranticoagulation.

The treatment site may be any blood vessel. The most acute such bloodvessels are coronary blood vessels. The coronary blood vessel may be anatural artery or an artificial artery, such as a vein graft forarterial bypass.

The step of administering includes delivering the congener in acontrolled manner over a sustained period of time, and comprisesintrapericardially or transpericardially extravascularly delivering thecongener to the coronary blood vessel. Methods of delivery comprise (i)either intrapericardially or transpericardially infusing the congenerthrough a percutaneously inserted catheter extravascularly to thecoronary blood vessel, (ii) iontophoretically delivering the congenertranspericardially extravascularly to the coronary blood vessel, and(iii) inserting extravascularly to the coronary blood vessel an implantcapable of extended time release of the congener. The last method ofdelivery includes percutaneously inserting the implant proximatelyadjacent, onto, or into the pericardial sac surrounding the heart, andin a particular, comprises surgically wrapping the implant around a veingraft used for an arterial bypass. The extravascular implant may be abiodegradable controlled-release polymer comprising the congener.

Broadly, our invention includes in respect to the heart a method oftreating it which comprises administering a cardio-active orcardio-vascular active drug from the pericardial space. Suitably thecardio-active or cardio-vascular active drug is selected fromvasodilator, antiplatelet, anticoagulant, thrombolytic,anti-inflammatory, antiarrhythmic, inotropic, antimitotic, angiogenic,antiatherogenic and gene therapy bioactive agents.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be more completely and easily understood whentaken in conjunction with the accompanying drawings, in which:

PIG. 1 is an illustration of the heart and a percutaneously insertedintrapericardial drug infusion catheter for intrapericardial delivery ofnitrovasodilator to epicardial coronary arteries in accordance with thisinvention.

FIG. 2 is an illustration of the heart and a percutaneously insertedintrapericardial drug delivery implant for intrapericardial delivery ofnitrovasodilator to epicardial coronary arteries in accordance with thisinvention.

FIG. 3 is an illustration of the heart with coronary artery bypass veingraft and an extravascular biodegradable polymer spiral-wrap implant forcontrolled release of nitrovasodilator to the vein graft in accordancewith this invention.

FIG. 4 is a representative recording of aortic pressure, phasic and meanflow velocity in the left anterior descending coronary artery, andpulmonary arterial pressure explained in Example 1.

FIG. 5A shows dosage of sodium nitroprusside (SNP, μg/kg/min) requiredto abolish cyclic flow reductions given intravenously (IV) orintrapericardially (IP), as explained in Example 1.

FIG. 5B shows change in frequency of cyclic flow reductions (CFR's/30minutes) after each dose of sodium nitroprusside (SNP, μg/kg/min) givenintravenously (IV) or intrapericardially (IP), as explained in Example1.

FIG. 6 shows changes in mean aortic pressure (AOM, mmHg), cardiac output(CO, L/min), peripheral vascular resistance (PVR, units), and pulmonaryarterial pressure (PAP, mmHg) after each dose of sodium nitroprusside(SNP, μ/kg/min) given intrapericardially (IP) or intravenously (IV), asexplained in Example 1.

FIG. 7A shows percent change in ex-vivo platelet aggregation induced bycollagen at 20 μg/ml in platelet-rich plasma obtained from systemiccirculation before and after each dose of sodium nitroprusside (SNP,μg/kg/min) given intravenously (IV) or intrapericardially (IP), asexplained in Example 2.

FIG. 7B shows percent change in ex-vivo platelet aggregation induced bycollagen at 20 μg/ml in platelet-rich plasma obtained from coronarycirculation (coronary sinus) before and after each dose of sodiumnitroprusside (SNP, μg/kg/min) given intravenously (IV) orintrapericardially (IP), as explained in Example 2.

FIG. 8 is a representative recording of aortic pressure and phasic andmean flow velocity in the left anterior descending coronary artery (LAD)after N^(G) -monomethyl-L-arginine (L-NMMA) was given into the leftatrium at 5 mg/kg, after sodium nitroprusside (SNP) was givenintrapericardially at 0.5 μg/kg/min, and after oxyhemoglobin (HbO₂) wasgiven into the LAD CORONARY ARTERY at 200 μg/kg/min, as explained inExample 3.

FIG. 9 shows changes in frequency of cyclic flow reductions (CFR's/30minutes) in the left anterior descending coronary artery (LAD) afterN^(G) -monomethyl-L-arginine (L-NMMA) was given into the left atrium at5 mg/kg, after sodium nitroprusside (SNP) was given intrapericardiallyat 0.5 μg/kg/min, and after oxyhemoglobin (HbO₂) was given into the LADcoronary artery at 200-600 μg/kg/min., as explained in Example 3.Compared to L-NMMA, *p<0.01; compared to SNP, **p<0.01.

FIG. 10 schematically shows a transpericardial nitrovasodilator drugdelivery catheter in place for use in accordance with this invention.

FIG. 11 schematically shows a longitudinal section of a portion of thetranspericardial nitrovasodilator drug delivery catheter of FIG. 10.

FIG. 12 schematically shows a cross section of the portion of thetranspericardial nitrovasodilator drug delivery catheter of FIG. 11.

FIG. 13 schematically shows a bottom view of a distal portion of thetranspericardial nitrovasodilator drug delivery catheter of FIG. 10.

FIG. 14 schematically shows a longitudinal section of anintrapericardial nitrovasodilator drug delivery catheter for delivery ofgaseous nitric oxide to epicardial coronary arteries in accordance withthis invention, schematically connected with a gas supply and controlsystem.

FIG. 15 schematically shows a cross section of a proximal part of theintrapericardial nitrovasodilator drug delivery catheter of FIG. 14.

FIG. 16 schematically shows a cross section of a distal part of theintrapericardial nitrovasodilator drug delivery catheter of FIG. 14.

FIG. 17 schematically shows an iontophoretic transpericardialnitrovasodilator drug delivery catheter in place for use in accordancewith this invention.

FIG. 18 schematically shows a longitudinal section of a portion of theiontophoretic transpericardial nitrovasodilator drug delivery catheterof FIG. 17.

FIG. 19 schematically shows a cross section of the portion of theiontophoretic transpericardial nitrovasodilator drug delivery catheterof FIG. 17.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Our invention involves a method of treating blood vessels in a mammal,which comprises the extravascular administration, adjacent andsite-specific to a blood vessel in the mammal, especially a human, of abioactive agent capable of one or more of the effects of (a) lysis of aplatelet thrombus with restoration of blood flow, (b) inhibition ofplatelet adhesion and aggregation at the site(s) of vessel injury, and(c) vasodilation of the vessel at the injury site(s) to maintain bloodflow through the vessel, at a dosage rate effective to promote thedesired local therapeutic effect upon the vessel at the vessel injurysite(s), but less than sufficient to generalize these effectssystemically. The bioactive agent preferably is a congener of anendothelium-derived bioactive agent, including nitric oxide, sodiumnitroprusside, nitroglycerin and prostacyclin. The method ofadministration includes controlled delivery of the bioactive agent overa sustained period of time. Typically, the site-specific dosage rate issignificantly lower than a systemic dosage rate necessary to promote thetherapeutic effects at the site(s).

When the bioactive agent is sodium nitroprusside and the site of bloodvessel treatment is the site of endothelial injury and thrombusformation, the therapeutic effect is lysis of the thrombus withrestoration of blood flow, inhibition of platelet aggregation adjacentto the injury site(s) without promoting systemic anticoagulation, andvasodilation adjacent to the site(s) to maintain blood flow through thevessel without promoting systemic hypotension. The method is alsoeffective to promote vasodilation and prevent platelet thrombusformation, as where the site is the site(s) of a surgical procedure thatinjures the vessel, such as a PTCA procedure or a CABG operation. Thusthe method is effective for treating acute thrombosis and chronicrestenosis. When the bioactive agent is sodium nitroprussideadministered extravascularly and adjacent to the treatment site(s), adosage rate of from about 0.1 to about 3.0 μg/kg/min is effective toproduce at least one of the desired therapeutic effects.

The method of administration includes infusion of the bioactive agentextravascularly and adjacent the vessel at the specific site(s). In apreferred application, the vessel treated is a coronary blood vessel andbioactive agent delivery is by an infusion catheter, the distal outletof which is percutaneously introduced into the pericardial sacsurrounding the heart of the mammal. Preferably the distal outlet is ofsmall size, suitably less than 1.5 mm in outer diameter, is made of amaterial that is nonreactive to adjacent tissues (suitably a siliconerubber polymer) is nontraumatic to adjacent tissues (suitably a`pig-tail` tip design) and is effective for distributing the bioactiveagent at the treatment site onto the extravascular surface of the targetvessel(s). Referring now to FIG. 1, there is illustrated a the humanheart 1 showing the epicardial coronary arteries 3, the pericardial sac4 enveloping the heart, and pericardial fluid 5 bathing the heart withinthe pericardial sac. One of the coronary arteries 3 is indicated to bestenosed at 3'. Below the heart is the diaphragm musculature 6. In thechest of the patient in front of the heart is the sternum 7 and thelower extension thereof called the xiphoid process. Shown percutaneouslyinserted below the xiphoid process is a subxiphoid introducer 8 whichhas pierced the pericardium 4. Carried within the subxiphoid introducer8 is a thereby percutaneously inserted intrapericardial nitrovasodilatoragent infusion catheter 2. Catheter 2 includes a catheter pig-tail 9which secures infusion catheter 2 within pericardium 4, and has one ormore distal side holes indicated on both sides of the lead line ofreference numeral "9" for delivery of the infused nitrovasodilatoragent. Fluidly connected to the end of infusion catheter 2 external tothe chest is external drug infusion pump 10 for delivery ofnitrovasodilator agent intrapericardially and extravascularly to theepicardial coronary arteries 3, as indicated schematically by the arrows11. The nitrovasodilator agent forms part of the bath in which the heartis bathed and the nitrovasodilator agent is delivered extravascularly,that is, to the outside of the vessels, for outside-in diffusion intothe vessels.

The method of administration includes percutaneously or surgicallyinserting, extravascularly and adjacent the vessel at the site oftreatment, an implant capable of extended time controlled-release of thebioactive agent. Preferably the implant includes a biodegradable polymercomprising the bioactive agent with controlled-release properties (see,for example, U.S. Pat. No. 5,099,060 and U.S. Pat. No. 4,980,449,incorporated herein by reference). The implant may be fiber-tipped fordistribution of the bioactive agent to the treatment site from thebiodegradable fiber tips. Referring to FIG. 2, an implant isillustrated. A heart 1 as in FIG. 1 has epicardial coronary arteries 3,pericardial sac 4, pericardial fluid 5, diaphragm 6 and sternum 7. Oneof the coronary arteries 3 is indicated to be stenosed at 3'. Shownpercutaneously inserted below the xiphoid process of sternum 7 is asubxiphoid implant introducer 13, which has pierced the pericardium 4.Carried with in the implant introducer 13 is a thereby percutaneouslyinserted intrapericardial nitrovasodilator agent delivery implant 12comprising nitrovasodilator agent/biodegradable polymer implant fibers14 for intrapericardial release of nitrovasodilator from the erodiblepolymer extravascularly to the epicardial coronary arteries 3, asindicated schematically by the arrows 15. Suitable other forms of animplant for percutaneous pericardial extravascular insertion areintrapericardial microparticles and a sponge matrix, all comprising abiodegradable polymer.

The implant suitably may comprise a wrap for a blood vessel at the siteof treatment, the wrap comprising the bioactive agent. In a method ofthe invention directed to venous bypass graft treatment, the method ofadministration comprises surgically inserting around the vein graft animplant capable of extended controlled-release of the bioactive agent. Asuitable form of the implant for extravascular insertion is aspiral-wrap device comprising a biodegradable polymer. Preferably thespiral-wrap implant is of a calibrated inner diameter, suitably toprevent vein graft distention, and is isocompliant with the vein graft,suitably to match normal coronary artery compliance. Referring to FIG. 3is an illustration of the heart 1 showing the aorta 16, an epicardialcoronary artery 3, a proximal anastomosis site 17 and a distalanastomosis site 18 of a coronary artery bypass vein graft 19, and anextravascular biodegradable polymer spiral-wrap implant for controlledrelease of nitrovasodilator drug to the vein graft 20.

Referring to FIGS. 10-13, an epipericardial drug distributing catheterapparatus 30 is illustrated for distribution of a liquid carrying abioactive drug onto the pericardium for transpericardial delivery of thebioactive drug. The apparatus comprises an elongated catheter body 31having a proximal segment 32 and distal segment 33. The catheter body 31includes at least one lumen 35 extending thereinto and exiting thecatheter body through a plurality of radially extending first passages38 in distal segment 33. A balloon 45 is mounted to at least a portionof the exterior of the catheter body distal segment and envelopes firstpassages 38, providing a cavity 48 between balloon 45 and the distalsegment portion containing passages 38, so that passages 38 open intothe cavity. A catheter sheath 47 having a distal extremity surroundingat least the distal segment 33 of the catheter body 31. Upon extensionof distal segment 33 beyond sheath 47 as shown in FIGS. 10-13, balloon45 is able to expand. Balloon 45 has a height-to-width cross sectionalratio of less than unity when expanded, as shown, when outside acatheter, preferably a height-to-width cross sectional ratio of about0.5 or less, preferably about 0.25 or less. Balloon 45 preferably whenexpanded has a width from about one to about four inches (or about 2.5cm to about 10 cm) and a height of about 0.4 inch or less (about 1.0 cmor less, typically about 0.625 cm). Typically the diameter of sheath 47is about 0.4 inch or less (about 1.0 cm or less, typically about 0.625cm). Thus upon expansion the balloon is significantly wider than it ishigh, and may have a generally pancake shape.

A second lumen 34 catheter body 31 extends to a plurality of passages 36radially spaced from the first passages 38 and connect second lumen 34to the exterior of the distal segment 33. Balloon 45 is mounted to theportion of the exterior surface of the catheter body distal segmentabove the second passages 36 so as not to cover them. Thus, percutaneousinsertion and upon extension of distal segment 33 beyond sheath 47 andover the pericardium, a fluid introduced through first lumen 35 expandsthe balloon to press the radially opposite surface of the distal segmentagainst the pericardial tissue surface and a pressurized fluidintroduced into the second lumen exits the catheter onto the surfaceagainst which the distal segment is pressed. However, it is preferred toenvelop passages 36 within a vessel to more expediently control flowonto the pericardium. Thus apparatus 30 further comprises an expandablevessel 40 mounted to an exterior surface of the distal segment of thecatheter body adjacent and radially opposite balloon 45 and over thesecond passages 36, thereby providing a vessel chamber 42 between thevessel and the radially adjacent exterior surface of distal segment 33into which the second passages open. Vessel 40 has a height-to-widthcross sectional ratio of less than about unity when expanded and haspores 43 to allow passage of fluid from vessel 40 under influence of apressure gradient across pores 43, thereby providing flow communicationfrom second lumen 34 through second passages 36 into vessel chamber 42and out of vessel chamber 42 through pores 43, whereby upon percutaneousintroduction of the distal segment 33, a pressurized fluid introducedthrough first lumen 35 expands balloon 45 to press vessel 40 against thepericardial tissue surface, and a fluid introduced under pressure intosecond lumen 34 passes through the pores 43 of vessel 40 onto thesurface against which the distal segment is pressed. Expanded vessel 40preferably has a height-to-width cross sectional ratio is 0.5 or less,preferably about 0.25 or less. Vessel 40 preferably when expanded has awidth from about one to about four inches (or about 2.5 cm to about 10cm) and a height of about one-fourth inch (or about 0.625 cm) or less.Thus upon expansion vessel 40 is significantly wider than it is high,and may have a generally pancake shape. Suitably vessel 40 comprises asemi-permeable membrane and the pores are microporous.

In use of drug delivery catheter 30, sheath 47 with catheter 31 nestedtherein is advanced within an introducer under the xiphod process of thesternum 7 into the mediastinum 21 of the thoracic cavity 22 to aposition between pericardium 4 and the inner chest wall, as shown inFIG. 1. The distal end of catheter body 31 is advanced from sheath 47 toextend the vessel 40 and the balloon 45 beyond the distal extremity ofsheath 47 and dispose exterior portion 44 of vessel 40 againstpericardium 4 and orient balloon 45 facing the inner chest wall. A gasor liquid fluid, suitably air, is introduced through first lumen 35 andpasses therethrough into balloon 45, inflating balloon. This expandsballoon 45 into contact against the inner chest wall of the mediastinum.The relatively wider than vertical aspect of balloon 45 assists instabilizing the distal segment from rotation. Inflation also causesballoon 45 to press exterior portion 44 of vessel 40 against the surfaceof pericardium 4. A liquid fluid is introduced into first lumen 34 andpasses therethrough into vessel 40, expanding vessel 40 predominatelylaterally. The liquid passes from vessel chamber 42 through the outlets43 and emerges therefrom onto the surface of pericardium 4 fortranspericardial passage of a drug (bioactive drug) in solution in theliquid and entry of the drug into the pericardial fluid bathing theheart, from which it suitably comes into contact with the coronaryarteries for migration into the vessel wall for cardiovascular effect.

Referring to FIGS. 14-16, an apparatus 50 for intrapericardial deliveryof gaseous nitric oxide to the epicardial coronary arteries inaccordance with our invention is illustrated schematically. It comprisesan elongated catheter body 51 having a proximal segment 52 and a distalsegment 53, the catheter body including at least one lumen 55 extendingthereinto and exiting the catheter body through at least one firstpassage 58 in the distal segment, and a balloon 60 mounted to at least aportion of the exterior of the catheter body distal segment andenveloping the first passage 58, providing a cavity 62 between theballoon and the distal segment, the first passage 58 opening into cavity62. Balloon 60 preferably has a height-to-width cross sectional ratio ofless than unity when expanded, more preferably, a height-to-width crosssectional ratio of about 0.5 or less, preferably about 0.25 or less, andcomprises a semi-permeable membrane suitable for diffusion therethoughof a fluid supplied under pressure through the lumen to the passage.Apparatus 50 comprises a second lumen 54 that extends through the distalend 53 of catheter 51 for receiving a guidewire 57 therethrough. A tube59 surrounding at least a portion of catheter body 51 creates apassageway 65 therebetween. An introducer 63 surrounds at least aportion of catheter body 51 for introduction of distal segment 53 intothe thoracic cavity and extension of balloon 60 beyond the distalextremity of sheath 63 for disposition exteriorly of the sheath onguidewire 57.

In use of apparatus 50 for intrapericardial delivery of gaseous nitricoxide to the epicardial coronary arteries in accordance with ourinvention, gaseous nitric oxide supplied by tank 70 is carried byconduit 71 controlled by microvalve 72 actuated by a solenoid 73responsive to a pressure differential diaphragm 74 and is introducedinto catheter apparatus 50, of which distal segment 53 has beenintroduced through the pericardium 4 through introducer 63. The nitricoxide gas flows through passageway 65 and passes into balloon 60 whichit inflates. The nitric oxide resident in balloon cavity 62 passes fromcavity 62 through the gas permeable membrane of balloon 60 and entersthe pericardial fluid bathing the coronary arteries for treatment ofthem. Gas within balloon cavity 62 has an exit passage from ballooncavity 62 through openings 58 for withdrawal from the balloon throughlumen 55 into a gas return conduit 75 under the force of withdrawal pump76.

Referring to FIGS. 17-19, an apparatus for iontophoretic delivery of abioactive drug onto the pericardium for transpericardial delivery of thebioactive drug is depicted schematically. The device is similar to thedevice illustrated in FIGS. 10-12, and corresponding numbers indicatesimilar structure. An expandable vessel 40 mounted to an exteriorsurface of said distal segment of said catheter body adjacent andradially opposite balloon 45 and having a height-to-width crosssectional ratio of less than about unity when expanded comprises anexpandable iontophoretic pad 82 containing a bioactive substance. Thesecond lumen 34 (see FIG. 10) carries electrical leads 80, 81. Voltagecarrying lead 80 is connected to a charge plate 83 in front of which ispad 82 containing a repository of a bioactive drug. Pad 82 is attachedto the outer surface 41 of distal segment 33. Circumscribing theperimetry of pad 82 is negative electrode 84, electrically insulatedfrom charge plate 83 and pad 82 by electrode insulators 85, 86. Negativeelectrode 84 is coupled to the ground of lead 81. When pad 82 is placedin contact with the pericardium 4 and plate 83, a charge is providedover lead 80 to charge plate 83. An electric field is establishedbetween charge plate 83 and negative electrode 84. This electric fieldpenetrates through the pericardium as it flows from plate 83 toelectrode 84. The field passes through bioactive drug pad 82, andcharged bioactive drug molecules contained within pad 82 migrate frompad 82 and through pericardium 4 as the electric field traverses thepericardial membrane. The charge supplied to plate 83 is sufficient toestablish the iontophoretic circuit, but insufficient to disturb thetransmission of the cardiac impulse through the heart.

By use of the apparatus of this invention coronary arteries of the heartcan be treated by application of therapeutic substances to the exteriorsurface of the heart. Cardio-active and cardiovascular-active drugs forintrapericardial delivery can include vasodilator, antiplatelet,anticoagulant, thrombolytic, anti-inflammatory, antiarrhythmic,inotropic, antimitotic, angiogenic, antiatherogenic and gene therapyagents. As already mentioned, fluid injected into the pericardial spaceaccumulates in the atrioventricular and interventricular grooves. Sincethe epicardial coronary arteries are located in the grooves of theheart, a bioactive therapeutic substance delivered into the pericardialspace through the methodology and devices of this invention canaccumulate and be concentrated over the coronary blood vessels.

In the following examples, the method of this invention is demonstratedto be effective.

EXAMPLE 1 Materials And Methods

All procedures in this an the following examples were conductedaccording to the principles of the American Physiological Society.

Twenty mongrel dogs weighing 25-35 kg were anesthetized with sodiumpentobarbital (30 mg/kg given intravenously) and connected to amechanical ventilator. Plastic catheters were placed in the left carotidartery for monitoring blood pressures and in a cephalic vein foradministering fluids and drugs. A balloon-tipped thermodilution catheterwas placed through a jugular vein into the pulmonary artery formeasuring pulmonary artery pressure and cardiac output. A leftthoracotomy was performed in the fifth intercostal space, and the heartwas exposed through a small pericardial window. A plastic cuff was fixedto the edge of the incised pericardium to prevent the leakage of fluidfrom the pericardial sac, thus creating a pericardial well. A 1-2 cmsegment of the left anterior descending (LAD) coronary artery wascarefully exposed by dissection and nearby vessel branches were ligated.A miniature ultrasonic Doppler flow probe was placed around the proximalpart of the exposed LAD coronary artery to measure the velocity of bloodflow. An additional plastic catheter was positioned in the coronarysinus for collecting venous blood samples from the coronary circulation.

Basic hemodynamics were continuously recorded on a physiologic recorder,including heart rate, systolic and diastolic aortic blood pressures,systolic, diastolic, and balloon-wedge pulmonary artery pressures,phasic and mean blood flow velocities in the LAD coronary artery, andthermodilution cardiac output.

The endothelium of the LAD coronary artery was injured by squeezing theartery 10-20 times with cushioned forceps. A plastic constrictor wasplaced around the LAD coronary artery at the site of injury to occludethe vessel and reduce the phasic flow velocity to approximately 60% ofthe baseline level. Subsequently, cyclic flow reductions (CFR's)developed as a result of recurrent platelet adhesion, aggregation anddislodgement on the injured endothelial surface. These 20 dogs werefurther studied in three groups:

Group I. In six dogs, saline was dripped onto the surface of the exposedLAD coronary artery and into the pericardial well at a infusion rate of0.2 ml/min through a plastic catheter. The saline infusion was continuedfor 60 minutes and hemodynamics were recorded continuously. The animalswere then humanely killed by pentobarbital overdose.

Group II. In seven dogs, sodium nitroprusside (Abbott Labs, NorthChicago, Ill.) was administered via delivery catheter on theextravascular surface of the injured LAD coronary artery and allowed toaccumulate in the pericardial well. The intrapericardial dose of sodiumnitroprusside was started at 0.5 μg/kg/min. If CFR's were not affectedwithin 30 minutes, the dosage was increased to 3.0 μg/kg/min. A maximaldosage of 6.0 μg/kg/ min was given to the animals not responding to thetwo lower doses. The animals were killed 30 minutes after CFR's wereabolished or after the highest dose of sodium nitroprusside was givenfor 30 minutes in the manner described above.

Group III. In the remaining seven dogs, sodium nitroprusside wasadministered intravenously at the same dosage range described for GroupII. The animals were monitored and killed in the same manner asdescribed above.

Results

All values were expressed as the mean ± standard error of the mean. Aone-way analysis of variance with repeated measurements was used tocompare the frequency of CFR's and the hemodynamic changes obtained atdifferent time periods before and after each treatment. Student's t-testwas used compare values between two different groups (p<0.05 wasconsidered significant).

1. Effect of Nitroprusside on CFR's

Cyclic coronary flow reductions developed in all 20 dogs afterendothelial injury and the external constriction of the LAD coronaryartery. The reduction of coronary flow velocity caused by externalconstriction was similar among the 3 experimental groups of animals(phasic flow velocity reduced to 70.7±9.2% of baseline in Group I, to66.5±4.9% in Group II, and to 56.4±5.0% in Group III (p>0.05). Thefrequency of initial (baseline, no drug) cyclic flow reductions in thecoronary arteries was also similar among the 3 groups of animals. Theheart rate and aortic blood pressure did not change significantly afterthe development of CFR's. After 30 minutes of consistent CFR's, for allstudies, different interventions were then administered.

In the Group I studies, intrapericardial infusion of saline did notchange the flow pattern or CFR frequency in any of the 6 animals (0%effective).

In the Group II studies, intrapericardial infusion of sodiumnitroprusside (FIG. 4) abolished the CFR's within 10 to 30 minutes inall 7 animals (100% effective).

In the Group III studies, intravenous infusion of sodium nitroprussideabolished the CFR's within 10 to 30 minutes in 5 of 7 animals (71%effective).

As shown in FIG. 5A, the average dose of sodium nitroprusside requiredto abolish the CFR's was significantly lower when it was administeredintrapericardially than when it was given intravenously (1.6±0.5 vs.4.8±0.8 μg/kg/min, respectively). Referring to FIG. 5A, IP drug deliverycompared to IV drug administration, +p<0.01.

As shown in FIG. 5B, the frequency of CFR's was also significantly lowerin animals that received intrapericardial sodium nitroprusside than inanimals that received sodium nitroprusside at the same doseintravenously. Referring to FIG. 5B, compared to control values,*p<0.05, **p<0.01; compared to IV drug administration, +p<0.05,++p<0.01.

These data indicate that treatment with sodium nitroprusside protectsagainst CFR's in stenosed and endothelium injured coronary arteries andthat the effective dosage required to abolish CFR's is lower and moreeffective when it is given intrapericardially than when it is givenintravenously.

2. Effect Of Nitroprusside On Hemodynamics

Intrapericardial saline infusion (Group I) did not significantly changeaortic pressures, cardiac output, pulmonary artery pressures orperipheral vascular resistance. As shown in FIG. 6, sodium nitroprussideinfusion (Groups II and III) reduced aortic pressures and peripheralvascular resistance in a dose-dependent manner. Cardiac output andpulmonary artery pressures were not significantly affected by eitherintravenous or intrapericardial administration of sodium nitroprusside.Referring to FIG. 6, compared to the control values, *p<0.05, **p<0.01;compared to IP at 3.0 μg/kg/min, +p<0.01.

These data indicate that extravascular intrapericardial infusion ofsodium nitroprusside has an advantage over intravenous infusion inreducing the systemic hypotensive side-effects of sodium nitroprusside.

EXAMPLE 2 Effect Of Nitroprusside On Platelet Aggregation Methods andMaterials.

Ex-vivo platelet aggregation was performed before and 10 minutes afterthe administration of each dose of sodium nitroprusside in Groups II andIII. Blood samples were collected from the plastic catheters in theaorta and the coronary sinus and anticoagulated with 3.8% sodium citrate(9 volumes blood: 1 volume sodium citrate). Platelet-rich plasma wasobtained by centrifuging the whole blood sample at 200× g for 20 minutesat room temperature. The platelet count in platelet-rich plasma wasadjusted to 300,000/mm³. A four-channel platelet aggregometer (modelPAP-4, Bio-Data, Horsham, Pa.) was used for the assay. Collagen (Sigma,St. Louis, Mo.) was used as a platelet agonist. The degree of plateletaggregation was reported as a percentage of maximal increase of lighttransmission in platelet-rich plasma over that in platelet-poor plasma.

Results

As in Example 1, all values were expressed as the mean±standard error ofthe mean. A one-way analysis of variance with repeated measurements wasused to compare the frequency of the platelet aggregation valuesobtained at different time periods before and after each treatment.Student's t-test was used compare values between two different groups(p<0.05 was considered significant).

Sodium nitroprusside infusion (Groups II and III) inhibitedcollagen-induced platelet aggregation in a dose-dependent manner in boththe systemic circulation (FIG. 7A, compared to control level, *p<0.05,**p<0.01) and coronary circulation (FIG. 7B, compared to control level,*p<0.05). In the animals treated with extravascular intrapericardialsodium nitroprusside, the degree of inhibition of platelet aggregationin coronary circulation was higher than that in the systemic circulation(FIG. 7B).

These data indicate that inhibition of platelet aggregation in thecoronary circulation is greater with extravascular intrapericardialinfusion of sodium nitroprusside than when it is given intravenously andreduces the systemic side-effects of antiplatelet therapy, such asbleeding complications.

EXAMPLE 3 Effect of Nitric Oxide on CFR's Methods and Materials

This example was a study to determine the mechanisms involved in theaction of sodium nitroprusside. The same preparative procedure wasfollowed as in Example 1 for an additional group of five dogs (GroupIV), except that in these animals, plastic catheters were also placedinto the left atrium of the heart and into a branch of the LAD coronaryartery proximal to the exposed segment. The exposed LAD coronary arterywas mildly injured (3-5 vessel squeezes) and stenosed with a plasticconstrictor. An inhibitor of nitric oxide synthetase, N^(G)-mono-methyl-L-arginine (L-NMMA, Calbiochem, La Jolla, Calif.), wasadministered into the left atrium at 5 mg/kg to eliminate the productionof endogenous nitric oxide and induce CFR's. After 30 minutes ofL-NMMA-induced CFR's, sodium nitroprusside was administered via deliverycatheter on the extravascular surface of the injured LAD coronary arteryand into the pericardial well. If the CFR's were abolished by theintrapericardial infusion of sodium nitroprusside, oxyhemoglobin, ascavenger of nitric oxide, was administered into the LAD coronaryartery. Oxyhemoglobin was given at incremental doses of 200, 400, and600 μg/kg/min. If oxyhemoglobin restored the CFR's abolished byintrapericardial sodium nitroprusside, the animals were monitored for 30minutes to ensure the consistency of the CFR's and were then killed inthe manner described above.

Results

As in the prior examples, all values were expressed as the mean±standarderror of the mean. A one-way analysis of variance with repeatedmeasurements was used to compare the frequency of CFR's and thehemodynamic changes obtained at different time periods before and aftereach treatment. Student's t-test was used compare values between twodifferent groups (p<0.05 was considered significant).

Infusion of L-NMMA into the left atrium at a dose of 5 mg/kg causedCFR's in all 5 animals in Group IV. The mean aortic pressure increasedapproximately 20 mmHg following L-NMMA infusion. After 30 minutes ofconsistent CFR's, extravascular intrapericardial sodium nitroprussideinfusion at a dosage of 0.5 μg/kg/min abolished the CFR's within 10 to30 minutes in all 5 dogs (p<0.01, FIGS. 8 and 9). The mean aorticpressure returned to the level before L-NMMA was infused. Oxyhemoglobin,infused into the proximal LAD coronary artery 30 minutes after CFR'swere abolished with sodium nitroprusside, restored CFR's within 5 to 20minutes in all 5 dogs (p<0.01, FIGS. 8 and 9). An average dose of 320±80μg/kg/min of oxyhemoglobin was given to restore CFR's. The severity ofthe restored CFR's was similar to that of L-NMMA-induced CFR's in 3 of 5animals and slightly less than that of the initial CFR's in the other 2dogs. Mean aortic pressure was not significantly affected byoxyhemoglobin infusion.

These data indicate that nitric oxide does play an important role whenextravascular intrapericardial sodium nitroprusside abolishes coronaryCFR's.

Having now described in detail t he methodology of our invention, thosein the art will appreciate more than merely the detailed means describedfor implementing the invention, and our invention is not meant to belimited merely to these detailed implementations, but to allimplementations comprehended by our claims within the spirit of ourinvention.

We claim:
 1. A method of use of a congener of an endothelium-derivedbioactive composition of matter, which comprises administering saidcongener percutaneously to a site proximately adjacent the exterior of acoronary blood vessel at a therapeutically effective dosage.
 2. Themethod of use of claim 1 in which said congener is prostacyclin,prostaglandin E₁, a nitrovasodilator, or a combination thereof.
 3. Themethod of use of claim 2 in which said nitrovasodilator is nitric oxide,a nitric oxide donor agent, or a combination thereof.
 4. The method ofuse of claim 3 in which said nitric oxide donor agent is L-arginine,sodium nitroprusside, nitroglycerin, or a combination thereof.
 5. Themethod of use of claim 1 in which said congener is sodium nitroprusside.6. The method of use of claim 1 in which said treatment site is acoronary artery.
 7. The method of use of claim 1 in which said treatmentsite is a vein graft for arterial bypass.
 8. The method of use of claim1 in which said step of administering includes delivering said congenerin a controlled manner over a sustained period of time.
 9. The method ofuse of claim 1 in which said step of administering comprisesintrapericardially extravascularly delivering said congener to saidcoronary blood vessel.
 10. The method of use of claim 9 in which saidstep of administering comprises intrapericardially infusing saidcongener through a percutaneously inserted catheter extravascularly tosaid coronary blood vessel.
 11. The method of use of claim 1 in whichsaid step of administering comprises transpericardially extravascularlydelivering said congener to said coronary blood vessel.
 12. The methodof use of claim 11 in which said step of administering comprisestranspericardially infusing said congener through a percutaneouslyinserted catheter extravascularly to said coronary blood vessel.
 13. Themethod of use of claim 11 in which said step of administering comprisesiontophoretically delivering said congener transpericardiallyextravascularly to said coronary blood vessel.
 14. The method of use ofclaim 1 in which said step of administering comprises insertingextravascularly to said coronary blood vessel an implant capable ofextended time release of said congener.
 15. The method of use of claim14 in which said step of inserting said extravascular implant comprisespercutaneously inserting said implant proximately adjacent, onto, orinto the pericardial sac surrounding the heart.
 16. The method of use ofclaim 14 in which step of inserting said extravascular implant comprisessurgically wrapping said implant around a vein graft used for anarterial bypass.
 17. The method of use of claim 14 in which saidextravascular implant is a biodegradable controlled-release polymercomprising said congener.
 18. The method of use of claim 1 in which saiddosage is effective to provide one or more of the therapeutic effects ofpromotion of vasodilation, inhibition of vessel spasm, inhibition ofplatelet aggregation, inhibition of vessel thrombosis, and inhibition ofplatelet growth factor release, at said treatment sites, withoutinducing systemic hypotension or anticoagulation.
 19. The method of useof claim 1 in which said dosage is a rate from about 0.1 to about 3.0μg/kg/min.
 20. A method of use of a sodium nitroprusside composition ofmatter, which comprises percutaneously intrapericardially ortranspericardially supplying sodium nitroprusside to a coronary bloodvessel in a therapeutically effective dose.
 21. A method of use of acongener of an endothelium-derived bioactive composition of matter whichcomprises percutaneously intrapericardially or transpericardiallydelivering said congener to a coronary blood vessel at a therapeuticallyeffective dosage.